Cao Mingbo, Li Yuxuan, Su Xiaorui, Tang Yongchang, Ren Yupeng, Luo Jing, Yuan Feng, Yang Gaoyuan, He Zhiwei, Shi Zheng, Hu Ziyi, Liang Guirong, Zhang Qi, Deng Meihai, Yao Zhicheng, Lin Nan
Department of Hepatobiliary Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China.
Department of General Surgery, Qilu Hospital, Shandong University, Jinan China.
Drug Resist Updat. 2025 Sep;82:101271. doi: 10.1016/j.drup.2025.101271. Epub 2025 Jun 7.
Lenvatinib resistance (LR) profoundly exacerbates the prognosis of patients afflicted with advanced hepatocellular carcinoma (HCC). As pivotal mediators of intercellular communication, exosomes have been implicated in the development of LR. Nonetheless, the precise contributions of exosome-derived long non-coding RNAs (lncRNAs) to this phenomenon remain inadequately elucidated. Our prior investigations identified that lnc-FAM72D-3 is markedly up-regulated in the serum exosomes of HCC patients, yet its specific functions and underlying mechanisms remain only partially defined. In this study, we established lenvatinib-resistant HCC cell lines and organoids and demonstrated, through rigorous in vitro and in vivo experiments, that exosome-derived lnc-FAM72D-3 facilitates HCC progression and contributes to the phenomenon of LR. Mechanistically, lnc-FAM72D-3 augments the affinity of the E3 ubiquitin ligase HECTD3 for MBNL1, inciting lysine 48-linked ubiquitination and subsequent degradation of MBNL1. This degradation diminishes the interaction between MBNL1 and focal adhesion kinase (FAK), precipitating the de-nucleation of FAK and its activation by phosphorylation. The activated FAK subsequently reorganizes the cytoskeleton, markedly enhancing the proliferation, invasion, and stemness of HCC cells, thereby fostering LR. In summary, this investigation offers novel mechanistic insights into the regulatory role of exosomal lncRNAs in LR and posits a potential therapeutic strategy aimed at mitigating LR in patients with HCC.
乐伐替尼耐药（LR）严重恶化晚期肝细胞癌（HCC）患者的预后。作为细胞间通讯的关键介质，外泌体与LR的发生有关。然而，外泌体来源的长链非编码RNA（lncRNAs）对这一现象的确切作用仍未得到充分阐明。我们之前的研究发现，lnc-FAM72D-3在HCC患者血清外泌体中显著上调，但其具体功能和潜在机制仍仅部分明确。在本研究中，我们建立了乐伐替尼耐药的HCC细胞系和类器官，并通过严格的体外和体内实验证明，外泌体来源的lnc-FAM72D-3促进HCC进展并导致LR现象。机制上，lnc-FAM72D-3增强E3泛素连接酶HECTD3对MBNL1的亲和力，引发赖氨酸48连接的泛素化及随后MBNL1的降解。这种降解减少了MBNL1与粘着斑激酶（FAK）之间的相互作用，促使FAK去细胞核并通过磷酸化激活。激活的FAK随后重组细胞骨架，显著增强HCC细胞的增殖、侵袭和干性，从而促进LR。总之，本研究为外泌体lncRNAs在LR中的调节作用提供了新的机制见解，并提出了一种旨在减轻HCC患者LR的潜在治疗策略。
